Epigenetic Regulators as Therapeutic Targets in Pancreatic Ductal Adenocarcinoma

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review provides an overview of epigenetic regulation in pancreatic ductal adenocarcinoma (PDAC), integrating chromatin modifiers, non-coding RNAs, tumor microenvironment remodeling, and therapeutic targeting strategies. However, several areas require refinement to enhance clarity, and readability.

1. Figure 1 appears incomplete and does not offer PDAC-specific insights. Panels 1A and 1B are confusing and seem to show only DNA methylation and non-coding RNAs structure without clearly illustrating epigenetic dysregulation or its role in PDAC progression. In addition, the legend lacks sufficient detail and mechanistic explanation.
2. Although the authors include a figure showing inhibitors used in PDAC, a mechanistic figure illustrating the role of epigenetic regulation in PDAC progression would greatly improve clarity.
3. The roles of KDMs and DUBs in maintaining euchromatin are not clearly shown in Figure 1 or explained in lines 159–160. The figure should depict how these enzymes support transcriptionally active chromatin.
4. Information on DNA methylation writers, erasers, and readers in PDAC is insufficient. The table provides only brief and incomplete details and does not explain how these factors function mechanistically in PDAC. More comprehensive description is needed.
5. The synergy between DNMT inhibitors and PARP inhibitors in cancer, and its relevance to PDAC, should be briefly explained. Line no 244.
6. The authors should discuss the limitations of epigenetic inhibitor therapies, including treatment failures, resistance mechanisms, toxicity, and barriers to clinical efficacy.

Author Response

Response attached in a word file.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

This review focuses on discussion of the current understanding of the role that epigenetic factors play in determining pancreatic cancer tumor behavior, promote spread of the disease and impart therapy resistance. Growing evidence indicates that alteration of epigenetic regulation plays an important role in pancreatic cancer biology, The review discusses the key epigenetic regulators and their potential as targets for novel therapeutic approaches to treat pancreatic cancer.

 

Overall, the review on current understanding of the epigenetic regulatory mechanisms involved in pancreatic cancer biology, and the summary of potential therapeutic targets and pathways is considered to be a highly valuable resource to the pancreatic cancer research community.

 

I would recommend the following points be addressed to improve the readability of the manuscript, and perhaps to address an omission of one potentially important player that should be considered in the epigenetic regulatory landscape of pancreatic cancer biology.

 

Comments:

 

1. Line 142: the introduction of the definition of the PRC2 abbreviation comes after (line 162) its first use on line 142. Please move the definition to the first use.
2. Line 143 - the introduction of the definition of the EZH2 abbreviation comes after (line 162) its first use on line 143. Please move the definition to the first use.
3. Line 143 - the BET abbreviation definition comes after (line 157) its first use on line 143. Please move the definition to the first use. Then the definition is repeated on line 316. The abbreviations definitions should only be used for the first use of the terms.
4. Line 144- the CPB/p300 abbreviation used on line 144 is only defined later on line 301. Line 197- seems like this sentence needs to be supported by one or more references
5. Line 199 – likewise, this sentence could be supported by one or more references.
6. Line 148 – The PDAC abbreviation is defined in the figure title, but it is also defined in the first sentence of the main body of the text. Is it necessary to repeat the definition?
7. Line 252 - The PDAC abbreviation is defined in the figure title, but it is also defined in the first sentence of the main body of the text. Is it necessary to repeat the definition?
8. Line 426 – the EMT abbreviation is defined in its first use on line 284. It is not necessary to repeat the definition on line 426.
9. Line 419 – HOTAIR is not defined or references in its first use in the manuscript.
10. Line 425 – MALAT1 is not defined in its first use in the manuscript.
11. Line 440 – HOTTIP is not defined in its first use in the manuscript.
12. Line 522 – The PDAC abbreviation definition is repeated here, but it defined in the first sentence of the main body of the text. Is it necessary to repeat the definition?
13. Line 467 – HDAC is defined here, but used throughout the manuscript, and first defined on line 167 in section 1.
14. Line 481 – BET is defined here, but first defined on line 157.
15. Line 550- seems that several terms are defined again, (DNMT is defined on lines 395 and 496), HDAC is defined first on line 167 in section 1, BET is defined first on line 157, but should be defined on line 143.
16. I am surprised that HMGA1 is not mentioned anywhere in this review, given that its role in pancreatic cancer biology is well-documented, it is strongly overexpressed pancreatic cancer cells, and it is a chromatin modulator that can potentially have strong influences on the epigenetic regulatory machinery.

Author Response

Response attached in a word file.

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

Critique

Epigenetic regulation represents a mechanism other than genetic mutation to mediate quick response to environmental and therapeutic pressures for reshaping tumor behavior, spread, and therapy resistance. Based on their functional role in adding, recognizing or removing chemical modifications on DNA or histone proteins that regulate chromatin structure and gene expression, epigenetic regulators are categorized as writers, readers, and erasers. Targeting pancreatic cancer, the authors summarize recent advance in pharmacological targeting of epigenetic regulators and discuss the rationale for combination strategies through the integration of epigenetic inhibitors with cytotoxic agents, targeted therapies, and immunotherapies. In addition, they emphasized emerging experimental platforms combined with multi-omic profiling and computational approaches to identify biomarkers of response and optimized therapeutic design. In summary, this review frames epigenetic regulation as a central factor in pancreatic cancer progression and a potential avenue for therapeutic intervention, critically evaluating both preclinical and clinical evidence supporting epigenetic regulators as pharmacological targets.  To further enhance the scientific depth and translational relevance of this review. I offer the following suggestions:

1. Authors would be encouraged to summarize recently published review articles in this area to clearly distinguish the novelty, value, and significance of the present work from existing literature.
2. For aberrant methylation in PDAC as diagnostic and circulating biomarkers, the authors would be encouraged to discuss the strengths such as potential for early diagnosis, complementary to existing markers etc., and limitations such as low sensitivity for early-stage tumor, standardization challenges etc.
3. Figure 2 provides an overview of epigenetic drugs investigated in preclinical and clinical trial studies for PDAC treatment and summarize their therapeutic applications. The authors should clarify the scientific rationales underlying development of first-, second, and third-generation epigenetic inhibitors. In addition, it would be important to discuss whether the third-generation epigenetic inhibitors improved efficacy, selectivity, safety, or pharmacokinetic properties compared with earlier compounds. If such improvements are not consistently observed, the authors would be encouraged to outline the key challenges and propose future directions for the development of next-generation epigenetic therapies in PDAC.
4. Some EZH2 inhibitors have received FDA approval for the treatment of certain cancers or have demonstrated activity in early-phage clinical trials. However, their efficacy in PDAC has been limited or not clearly established. The authors are encouraged to provide a mechanistic discussion of the potential reasons underlying this lack of therapeutic benefit in PDAC and outline rational future directions.
5. It would be important to systemically introduce the different classes of CBP/p300 acetyltransferases inhibitors that have been developed based on distinct functional mechanisms and summarized the evidence supporting their evaluation in PDAC. Clarifying their mechanisms of action, preclinical efficacy, and current stage of clinical development would strengthen the scientific depth and translational relevance of this section.
6. In addition to BET proteins family, CBX proteins, and BMI1, many other epigenetic readers have been identified. The authors are encouraged to discuss their potential role in PDAC.
7. In addition to the brief introduction, the authors are encouraged to discuss the progress in exploring ncRNA as both therapeutic targets and tools in PDAC treatment. Specifically, it would be valuable to highlight recent advances in preclinical and clinical studies and strategies.
8. Given the intrinsic resistance of PDAC resistance to immunotherapy, it would be valuable for the authors to discuss strategies for targeting epigenetic regulators to enhance tumors immunogenicity and overcome immune evasion. Such a discussion could highlight how modulation of DNA methylation, histone modifications, or non‑coding RNAs might sensitize PDAC to immune checkpoint inhibitors, thereby advancing the efficacy of immunotherapeutic approaches in this challenging malignancy.

Author Response

Response attached in a word file.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The author provided satisfactory responses for my comments.

Reviewer 3 Report

Comments and Suggestions for Authors

The authors have addressed each issue point by point. The revised version demonstrates substantial improvements in clarity, rigor, and overall quality.